Varicella Zoster Virus: From Chickenpox to Shingles
VZV affects patients both young and old. Here’s how to manage the associated ocular complications.
Despite the relatively recent advent of multiple vaccines for both chickenpox and shingles, the overall incidence of herpes zoster is on the rise. This article will review the ocular complications associated with varicella zoster virus (VZV) in both children and adults, as well as discuss potential treatment options for shingles and postherpetic neuralgia.
William Marcolini, OD
This course is COPE approved for 2 hours of CE credit. COPE ID 36847-AS. Check with your local state licensing board to see if this counts toward your CE requirements for relicensure.
This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.
Dr. Marcolini has no relationships to disclose.
As primary care optometrists, we often see pediatric patients with chickenpox or older individuals with herpes zoster--commonly known as shingles. Despite the relatively recent advent of multiple vaccines for both chickenpox and shingles, the overall incidence of herpes zoster is on the rise.1
In an effort to provide the best possible care, this article will review the ocular complications associated with varicella zoster virus (VZV) in both children and adults, as well as discuss potential treatment options for shingles and postherpetic neuralgia.
Upon primary infection, VZV causes the development of chickenpox in children and young teenagers. Most children become infected with VZV between the ages of five and 10 years.2 Typically, this initial infection--coupled with intermittent environmental exposure--provides the patient with a lifetime of immunity against the recurrence of chickenpox.2
VZV is one of eight strains of herpes viruses known to infect humans. Most often, the primary infection persists for two weeks and causes vesicular, macular and papular eruptions on the face and trunk that crust over within a few weeks. Fever and general malaise are the most common symptoms, with the potential for long-term cutaneous scarring.
Although the course of chickenpox is usually benign, there are exceptions. In fact, associated cases of pneumonia, encephalitis and even death have been reported in the literature.2
VZV is highly contagious. In the past, parents have hosted "pox parties" in an effort to expose their kids to other infected children. This would ensure simultaneous infection throughout the household and confer immunity going forward.
Shingles manifest following the reactivation of latent VZV during adulthood. The Centers for Disease Control and Prevention (CDC) estimates that 500,000 to one million cases of shingles are reported each year. Shingles typically present with a characteristic rash that respects the midline. Typically, this rash is found in the lower thoracic region, but also may be located on the scalp, forehead and periorbital structures.
Both chickenpox and shingles are caused by VZV. A child is first infected when the virus enters the respiratory mucosa or the conjunctiva. After the initial varicella infection, the virus becomes dormant. Subsequent reactivation is predicated on certain triggers. Such triggers are heavily influenced by the condition of the host, and are believed to include the presence of an immunocompromising condition, use of immunosuppressive medications or long-standing emotional stress.2,3
During the latency period, the virus remains in the dorsal root ganglia. The dorsal root ganglia are located throughout the body and along the spinal cord, and are part of the afferent sensory system. This explains how the virus can travel via axonal transport to the skin or mucous membranes. As optometrists, we are most concerned with eruptions along the trigeminal dermatome. However, just 13% to 20% of all cases involve one of the 12 cranial nerves, including the trigeminal (CN V).3
The primary clinical trial for the herpes zoster vaccine Zostavax (live zoster virus, Merck) included more than 38,000 adults aged 60 to 80 years who had previous history of shingles.4 Subjects who were treated with Zostavax were 51% less likely to develop shingles and 66% less likely to experience postherpetic neuralgia.4 Further, patients who still developed shingles following treatment with Zostavax exhibited less severe signs and symptoms.4 The researchers also determined that the efficacy of Zostavax declined proportionately with advanced age.
Another study of 22,000 adults aged 50 through 59 years showed that the risk of shingles was reduced by 69.8% following the administration of Zostavax.2 Although the FDA approved Zostavax for individuals age 50 years and older in March 2011, CDC officials recommended that the vaccine only be used in patients 60 years and older.2 This recommendation likely is explained, in part, by lingering concerns about vaccine supply and a lower overall risk of herpes zoster in the 50 to 59 years of age cohort.
Ocular Manifestations of Chickenpox
Eighty-five percent of chickenpox infections occur before age 15.2 Optometrists with significant pediatric populations will see a larger volume of ocular complications. Vesicular eruptions can occur externally, along the periorbital skin around the eyelids. The eyelids often become infected, and scarring and/or pockmarks may result. Further, the conjunctiva can be infected by vesicles as well as a non-specific papillary conjunctivitis.
Most significantly, the cornea can be scarred by vesicular eruption.5 Similar to the dendritic appearance caused by herpes simplex virus (HSV) keratitis, active varicella can invade the cornea and cause punctate or dendritic keratitis (see "How to Differentiate Herpes Simplex from Varicella Zoster," above).5
An immune-mediated disciform keratitis, with or without uveitis, may be documented.5 Cases of cranial nerve palsies, retinopathy and optic neuropathy also have been reported. Carefully examine each ocular structure--from the cornea to the retina--in all pediatric patients who present with chickenpox.
Ocular Manifestations of Shingles
In most instances, herpes zoster patients who present to my office have already been diagnosed with active shingles. Occasionally, the patient exhibits the characteristic unilateral, dermatomal rash on the forehead, periorbital region and nose. If the rash is present on the nose, the virus has spread sufficiently enough along the V1 nasociliary branch of the trigeminal nerve. This presentation, known as Hutchinson's sign, indicates a high probability of ophthalmic involvement.5 It must be noted that the absence of Hutchinson's sign should in no way be reassuring, as significant ocular involvement is often seen without frank evidence of this indicator.
Because the outbreak occurs along the trigeminal dermatome, the rash respects the midline and manifests on only one side of the patient's face or scalp.5
Whether you make the initial diagnosis or participate in a consult, your clinical responsibilities are the same. The eye must be inspected from cornea to retina, with a special emphasis on intraoc-ular pressure. The goal is to arrest viral replication, control inflammation, prevent scarring and educate the patient about the possibility of postherpetic neuralgia.
* Symptoms. Shingles presents with prodromal symptoms a few days before the onset of a macular rash, which rapidly progresses to papular and vesicular eruptions within 24 hours.5 The prodromal symptoms include pain, redness, hypesthesia, fever, malaise and headache.5 While these symptoms can be associated with a host of diseases, it is the characteristic rash and respect of the midline that makes the diagnosis straightforward. Occasionally, an immunologic test from vesicular fluid or a serologic workup that reveals a high IgM titer against VZV is necessary to confirm a confusing case.
Inform the patient that the rash usually continues to develop and proliferate for three to four days. The acute phase often lasts two weeks or more, until the rash crusts over.5 Acute pain tends to lessen during the course of the disease; however, pain may persist in the affected dermatome for months to years--a condition known as postherpetic neuralgia.6
* Pertinent anatomy. Typically, shingles reactivation occurs in the thoracic region. Less commonly, it may affect the trigeminal nerve. Herpes zoster ophthalmicus (HZO) is defined as a reactivation of VZV that originates from the trigeminal ganglion and includes ocular involvement. The trigeminal nerve provides both sensory and motor functions. It is primarily responsible for facial sensation.
The trigeminal nerve has three main branches: the V1 ophthalmic branch (sensory), the V2 maxillary branch (sensory) and the V3 mandibular branch (motor for chewing). The V1 ophthalmic relays sensory information from the scalp, forehead, eyelids, periorbital skin, nose and, most importantly, the cornea and conjunctiva.
The V1 branch is further divided into the frontal, nasociliary and lacrimal nerves. The frontal nerve is most commonly affected by VZV reactivation, which is why shingles often appears on the forehead. The nasociliary branch innervates the skin of both eyelids as well as the tip of the nose, conjunctiva, sclera, cornea, iris and choroid.5
Considering the extensive nerve involvement, it becomes increasingly evident that the virus easily can spread to any nearby ophthalmic component. That's why I examine herpes zoster patients in a similar fashion as victims of blunt force trauma--from the adnexa to optic nerve.
When the forehead and scalp are affected (indicative of frontal nerve involvement), the upper eyelid may exhibit vesicles and edema. These symptoms often resolve without sequelae; however, if scarring results, lid retraction and exposure may develop.6 Associated conjunctivitis can be follicular or necrotizing, and may occasionally yield conjunctival vesicles and potential scarring.6 Also, the sclera can be involved with a scleritis or an episclerits.
* Herpes zoster ophthalmicus. Approximately two-thirds of HZO cases have corneal involvement.7 All layers of the cornea potentially can be infected--from the epithelium to the endothelium. Further, corneal involvement can occur during the acute event or years after the infection has subsided.7
The epithelial dendrite present in HZO often is termed a "pseudodendrite." The pseudodendrite may begin as clusters of swollen epithelial cells that are infected with live zoster virus.
At this stage, the inflamed lesion commonly is referred to as punctate epithelial keratopathy. Over time, the lesion resolves, develops anterior stromal infiltrates, or coalesces to form into a dendritiform pattern.6 In most instances, though, these lesions tend to resolve spontaneously over weeks without topical treatment.
A neurotrophic keratitis can be seen in patients who have corneal nerve damage. Because of decreased innervation and sensation, the cornea can develop a non-healing neurotrophic ulcer that is neither infectious nor inflammatory, and therefore must be managed differently. In general, patients with HZO are more likely to experience severely reduced corneal sensitivity than those with HSV keratitis.6 During evaluation, test corneal sensitivity with a simple cotton wisp to detect areas of denervation.
Stromal disease represents an immune reaction to retained viral antigen in the corneal epithelium, and is not a sign of active HZO. Nonetheless, resultant inflammation can yield devastating visual consequences. This immune reaction can occur within three to four months following the reactivation of varicella, or it may present several years later.6,7 So, you may think of HZO as a reactivation of VZV, and stromal disease as a subsequent immune response to the reactivation.
HZO can cause anterior uveitis, iris atrophy, choroiditis, retinitis, optic neuritis and even acute retinal necrosis.6,7 A dilated fundus examination is of paramount importance in any suspected case of HZO. Be certain to investigate for inflammatory lesions or necrosis in the retina as well as optic nerve edema.
Additionally, it is essential to inspect the anterior chamber for the presence of cells and flare, because significant iridocyclitis can develop. Iridocyclitis usually presents within the first week of herpes zoster infection, but can be seen months after.6
HZO is notorious for causing chronic complications associated with recurrent inflammation, including increased intraocular pressure and/or trabeculitis.8 Such persistent inflammation is believed to be caused by the presence of inactivated viral antigens in the eye or ongoing low-grade viral replication.8-10
Treatment for Shingles
Primary treatment for active herpes zoster should be aimed at curtailing viral replication, minimizing inflammation, preventing secondary infection and limiting the potential for future postherpetic neuralgia. Ultimately, the location and the extent of ocular involvement will drive your treatment regimen.
* Oral antiviral therapy is a mainstay treatment for HZO, and should be initiated within the first 72 hours following diagnosis of herpes zoster.6 This accelerates resolution of the skin rash and lesions, shortens the period of lesion formation and viral shedding, and reduces the incidence of episcleritis, keratitis and iritis.6 Oral antiviral agents also appear to limit, but not prevent, the symptoms of postherpetic neuralgia. For patients who have scalp involvement or ocular complications that are limited to the eyelids, prescribe one of the following systemic treatment regimens:
- 800mg acyclovir five times a day for seven to 10 days.
- 1,000mg valacyclovir TID for seven days.
- 500mg famciclovir QD for seven days.
* Systemic corticosteroids, such as oral prednisone, are a useful adjunct to antiviral agents in patients who have moderate to severe pain. Patients on combination systemic steroids/antiviral therapy have been shown to experience shorter healing times and decreased pain during the acute infection period.6 But remember, immunocompromised patients are at risk for disseminated disease and should not be placed on systemic steroids.
Additionally, posterior uveitis and/or acute retinal necrosis must be managed aggressively with a combination of intravenous/oral antivirals and systemic steroids. These patients require immediate referral to a retina specialist for proper management.
* Topical agents in conjunction with oral antiviral therapy may be necessary if a herpes zoster patient exhibits conjunctival or corneal involvement, or develops a keratouveitis. However, because patient circumstances vary and viral response is not always predictable, there is no consensus on the clinical utility of topical treatment.
In the presence of conjunctival lesions, conjunctivitis or a corneal pseudodendrite, antibiotic ointments, such as erythromycin or bacitracin, may be used TID. In the past, antiviral ointments, such as Vira-A (vidarabine, Monarch Pharmaceuticals) QID, sometimes were used. (Vira-A ointment is no longer available in the US and has no generic equivalent.) Viroptic (trifluridine, Monarch Pharmaceuticals) also has been used in the past, but was not proven effective.
Generic ganciclovir ointment or Zirgan (0.15% ganciclovir ophthalmic gel, Bausch + Lomb) may be beneficial for individuals with active lesions; however, ganciclovir's role and clinical efficacy has not been formally established. Nonetheless, off-label applications of ganciclovir have demonstrated good activity against HSV, VZV, cytomegalovirus, Epstein-Barr virus and multiple strains of adenovirus.11
Once the corneal stroma is involved, permanent scarring and damage can occur. Thus, disciform keratitis must be treated promptly with topical corticosteroids. Prednisolone acetate 1% QID to Q4H is recommended, with a slow taper over a few months. Cycloplegic agents, such as scopolamine 0.25%, should be used two to four times daily.
Take note that topical antivirals have little to no effect on inflammation associated with elevated intraocular pressure and/or iridocyclitis. Instead, prescribe topical hypotensive agents for pressure control, as needed.
After the patient has recovered from the acute rash that characterizes HZO, he or she may experience pain in the affected dermatome that persists for weeks, months or even years. The pain from postherpetic neuralgia is often unbearable.
Approximately half of patients with shingles or postherpetic neuralgia describe their pain as "horrible" or "excruciating," ranging in duration from a few minutes to constant, on a daily or almost daily basis.1 In fact, there have been reports of suicide in elderly patients because of the unbearable pain.12
The mechanism that causes postherpetic neuralgia is not well understood. Injury to peripheral nerves and altered central nervous system signal processing may contribute to its onset. According to the CDC, "Pathologic observations thought to distinguish postherpetic neuralgia from uncomplicated zoster include axonal and cell body degeneration, atrophy of the spinal cord dorsal horn, scarring of the dorsal root ganglion and loss of epidermal innervation of the affected area."13 This neuronal damage might be caused by ongoing viral replication.13 Regardless of the exact mechanism, you may see herpes zoster patients who present with postherpetic neuralgia. In many instances, these individuals require timely referral to a pain management specialist.
Treatment for Postherpetic Neuralgia
While there is no specific treatment course for postherpetic neuralgia, several oral and topical pain management strategies could help alleviate patient discomfort. Use of Neurontin (gabapentin, Pfizer), Lyrica (pregabalin, Pfizer), NSAID analgesics, narcotics and/or tricyclic antidepressants (e.g., amitriptyline) may prove effective.
Further, topical options include: Zostrix (capsaicin cream 0.025%, Hi-Tech Pharmaceutical Co. Inc), Qutenza patch (capsaicin 8%, NeurogesX) and Lidoderm patches (lidocane 5.0%, Endo Pharmaceuticals) may be used as well.
Explanations for Increased Incidence
So, why has the number of herpes zoster cases increased during the last two decades, despite the availability of vaccines for both chickenpox and shingles? The higher disease incidence seems to be independent of the population's advancing age.
Interestingly, several studies indicated that the overall incidence of shingles started increasing before the chickenpox vaccine Varivax (live varicella virus, Merck) was introduced in the United States.1,14-16 Still, the underlying reasons for this increased prevalence are not well understood. Most importantly, however, no consistent evidence suggests that the increased incidence of shingles in the US has been accelerated by the widespread use of the varicella vaccine.1
It is worth mentioning that there have been cases of patients who actually have experienced a reactivation of herpes zoster following vaccination. Recently, researchers reported the case of a patient with a 3.5-year history of inactive herpes zoster who experienced a bout of keratouveitis two weeks after receiving Zostavax.17 The authors proposed that an increase in cell-mediated immunity was augmented by vaccine administration.17
Vexed by Vaccination?
Whether widespread vaccination for chickenpox and shingles ultimately is "good or bad" for patient care is beyond the scope of this article. Nonetheless, this point must--at the very least--be touched upon.
Critics have contended that the recent increase in shingles incidence has been caused by not allowing children to be exposed to VZV naturally at a young age-- effectively denying them a lifetime of immunity. According to this argument, widespread vaccinations may prevent both children and adults from having their natural immunity boosted because they no longer come into regular contact with infected individuals.
Additionally, some advocates believe that mass vaccination for what often is regarded as a benign childhood illness is neither necessary nor cost effective.18 In a recent article in the journal Vaccine, the authors argued that the varicella vaccination is less effective than the natural immunity experienced in pre-vaccine communities. Further, the researchers noted that mass vaccination isn't a cost-effective measure, because more money now must be spent treating the increased number of herpes zoster patients.18
Evidence-based medicine shows that mass vaccination does indeed lower the overall incidence of chickenpox and shingles in treated individuals. However, experts across many fields of the medical community still are determining the long-term, widespread impact of VZV vaccination upon the population as a whole.
As a primary eye care provider, you will encounter patients who inquire about the benefits of vaccination. You can inform them confidently that Zostavax is recommended for patients who are over the age of 60 or for those who have a history of shingles.
Treating herpes zoster can be both rewarding and frustrating--for you and the patient. It is important to recognize the signs and symptoms, and begin treat ment promptly. You must then monitor these patients closely and taper their medications accordingly. Finally, always remain vigilant about the possibility of postherpetic neuralgia.
Dr. Marcolini is in a group practice at Omni Eye Services in Iselin, N.J., and in private practice in Clinton, N.J.
- The United States Centers for Disease Control and Prevention. Shingles (Herpes Zoster). Available at: www.cdc.gov/shingles/hcp/ clinical-overview.html. Accessed January 16, 2013.
- The United States Centers for Disease Control and Prevention. Varicella. Available at: www.cdc.gov/vaccines/pubs/pinkbook/ downloads/varicella.pdf. Accessed January 16, 2013.
- Ragozzino MW, Melton LJ 3rd, Kurland LT, et al. Population-based study of herpes zoster and its sequelae. Medicine (Balti-more). 1982 Sep;61(5):310-6.
- Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005 Jun 2;352(22):2271-84.
- Lee WB, Liesegang TJ. Herpes Zoster Keratitis. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea, 2nd ed. Philadelphia: Elsevier Mosby; 2005:1075-89.
- Yanoff M, Duker JS. Infectious Keratitis. In: Ophthalmology, 2nd ed. Philadelphia: Mosby; 2004:469-81.
- Leisegang TJ. Corneal complications from herpes zoster ophthal-micus. Ophthalmology. 1985 Mar;92(3):316-24.
- Foster CS, Vitale AT. Herpes Viruses. In: Diagnosis and Treatment of Uveitis. Philadelphia: WB Saunders; 2002:317-23.
- Wenkel H, Rummelt V, Fleckenstein B, Naumann GO. Detection of varicella zoster virus DNA and viral antigen in human eyes after herpes zoster ophthalmicus. Ophthalmology. 1998 Jul;105(7):1323-30.
- Zaal MJ, Maudgal PC, Rietveld E, Suir EP. Chronic ocular zoster. Curr Eye Res. 1991;10 Suppl:125-30.
- Foster CS. Ganciclovir gel--a new topical treatment for herpetic keratitis. Availale at: www.touchbriefings.com/pdf/3200/foster.pdf. Accessed January 28, 2013.
- El-Ansary M. International Association for the Study of Pain. Chapter 24: Management of postherpetic neuralgia. Available at: www.iasp-pain.org/AM/Template.cfm?Section=Home&Template=/ CM/ContentDisplay.cfm&ContentID=12187. Accessed January 28, 2013.
- Harpaz R, Ortega-Sanchez IR, Seward JF. The United States Centers for Disease Control and Prevention. Prevention of Herpes Zoster: Recommendations of the Advisory Committee on Immunization Practices. Available at: www.cdc.gov/mmwr/preview/ mmwrhtml/rr5705a1.htm. Accessed January 16, 2013.
- Yawn BP, Saddier P, Wollan PC, et al. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007 Nov;82(11):1341-9.
- Donahue JG, Choo PW, Manson JE, Platt R. The incidence of herpes zoster. Arch Int Med 1995 Aug 7-21;155(15):1605-9.
- Hales CM, Harpaz R, Joesoef MR, Bialek SR. Herpes zoster in the Medicare population, 1991-2009: Assessment of trends, risk factors and the impact of the varicella vaccination program. Poster presented at: IDWeek 2012; San Diego: October 17-21 2012.
- Hwang CW Jr, Steigleman WA, Saucedo-Sanchez E, Tuli SS. Reactivation of herpes zoster keratitis in an adult after varicella zoster vaccination. Cornea. 2012 Nov 26. [Epub ahead of print]
- Goldman GS, King PG. Review of the United States universal varicella vaccination program: Herpes zoster incidence rates, cost-effectiveness, and vaccine efficacy based primarily on the Antelope Valley Varicella Active Surveillance Project data. Vaccine. 2012 Jun 1. [Epub ahead of print]
- Prince A. Infectious diseases. In: Behrman RE, Lkiegman RM (eds.). Essentials of pediatrics, 2nd ed. Philadelphia: WB Saun-ders;1994:297-394. .